1. Field of the Invention
The present invention relates to a pharmaceutical composition for treating an Fms-like tyrosine kinase 3 (FLT3) mutation-positive cancer, containing a nitrogen-containing heterocyclic compound or a salt thereof as an active ingredient, a mutant FLT3 inhibitor, and uses thereof.
2. Description of the Related Art
The Fms-like tyrosine kinase 3 (FLT3) is a protein belonging to the class III of receptor tyrosine kinases and has five immnunoglobulin-like motifs in the N-terminal extracellular domain and two kinase domains at the C-terminal. FLT3 is expressed on normal CD34-positive human bone marrow progenitor cells and dendritic progenitor cells and plays an important role in growth, differentiation or the like of these cells (Brown P, et al., European Journal of Cancer, Vol. 40, pp. 707 to 721, 2004). In addition, the ligand of FLT3 (FL) is one of cytokines that is expressed in bone marrow stroma cells and T cells to thereby have an effect on development of a number of hematopoietic lineage cells and stimulate growth of stem cells, progenitor cells, dendritic cells and natural killer cells through interactions with other growth factors.
FLT3 dimerizes when FL binds thereto, and then is activated by autophosphorylation. As a result, phosphorylation of AKT and ERK of PI3 and RAS signaling pathways is induced. FLT3 plays an important role in growth and differentiation of hematopoietic cells.
In normal bone marrow, the expression of FLT3 is limited to early progenitor cells, but in blood cancer, FLT3 is expressed at high levels or FLT3 undergoes gene mutation, thereby contributing to malignant growth of cancer through the activation of the signaling pathways. Examples of the blood cancer include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T cell ALL, myelodysplastic syndrome (MDS) and myeloproliferative disease (MPD).
Although several existing therapies exhibit successful results to some extent against AML among blood cancers, AML shows relapse and resistance in many cases and is therefore still refractory cancer with a 5-year survival rate of about 24% (in the United States) (American Cancer Society, Cancer Facts and Figures, pp. 9 to 24, 2012). One of causes for the relapse and resistance is genetic mutations of AML cells, among which a mutation of the FLT3 gene has been identified most frequently. Examples of FLT3 gene mutations include an Internal Tandem Duplication (ITD) mutation where a portion of the juxtamembrane domain is repeated, and a TKD mutation where amino acid residues located in the Tyrosine Kinase Domain (TKD) are changed to different amino acid residues by substitution, deletion or addition (American Cancer Society, Cancer Facts and Figures, pp. 9 to 24, 2012), and it is known that FLT3 is constitutively activated even in the absence of a ligand, thereby enhancing the growth of cancer cells.
Since the ITD mutation is known as a poor prognostic factor in AML, improvements of prognosis by existing chemotherapies have been attempted but there has been a difficulty therein. From such a situation, the NCCN Guidelines for the treatment of AML specify that participation in a clinical trial which can be the subject should be taken into account as one of treatment options. Further, also in the WHO classification 4th edition, the ITD mutation has been described as one of genetic mutations to be screened for diagnosis and treatment of AML.
The TKD mutation is known to show mutations or deletions of aspartic acid residue 835 (D835) and surrounding amino acid residues located particularly in the activation loop in AML, and there are also some reports that the TKD mutation is a poor prognostic factor. In addition, mutations of phenylalanine residue 691 (F691) and surrounding amino acid residues located in the gatekeeper domain known as one of the drug resistance mechanisms in other tyrosine kinases have also been recognized as the TKD mutation. In clinical trials for the treatment of AML by an FLT3-targeting drug, drug resistance of AML having both the ITD mutation and the TKD mutation is already known.
Since it is considered that inhibition of the activity of mutant FLT3, together with inhibition of the activity of FLT3, is important for the treatment and prognostic improvement of AML, the development of a pharmaceutical agent inhibiting FLT3 and mutant FLT3 have been conducted. For example, AC220 (Ambit Inc.) is a compound that selectively inhibits type III tyrosine kinases (FLT3, c-KIT, FMS, and PDGFR), and the development of a pharmaceutical agent that targets AML has been conducted (W02007/109120A). However, there is no report for a pharmaceutical agent that sufficiently inhibits the activity of mutant FLT3.
On the other hand, a nitrogen-containing heterocyclic compound or a salt thereof described in W02013/157540A has been known as an FLT3 inhibitor.